Hindawi Publishing Corporation Journal of Biomedicine and Biotechnology Volume 2011, Article ID 790871, 11 pages doi:10.1155/2011/790871

Review Article Extranodal NK/T-Cell : Toward the Identification of Clinical Molecular Targets

Christian Schmitt,1, 2, 3 Nouhoum Sako,1, 2 Martine Bagot,1, 2 Yenlin Huang,4 Philippe Gaulard,5, 6, 7 and Armand Bensussan1, 2

1 INSERM U976, 75010 Paris, France 2 Facult´e des Sciences, Universit´e Paris Diderot, 75013 Paris, France 3 Immunologie, Oncologie, et Dermatologie, INSERM U976, Hˆopital Saint-Louis, 1 avenue Claude Vellefaux, Pavillon Bazin, 75475 Paris Cedex 10, France 4 Department of Anatomic Pathology, Chang Gung Memorial Hospital, Gueishan 33305, Taiwan 5 INSERM U955, 94010 Cr´eteil, France 6 Facult´edeM´edecine, Universit´eParis-EstCr´eteil, 94010 Cr´eteil, France 7 Groupe Henri-Mondor, D´epartement de Pathologie, AP-HP, 94010 Cr´eteil, France

Correspondence should be addressed to Christian Schmitt, [email protected]

Received 30 December 2010; Accepted 24 February 2011

Academic Editor: John E. Coligan

Copyright © 2011 Christian Schmitt et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Extranodal natural killer (NK)/T-cell lymphoma of nasal type (NKTCL) is a malignant disorder of cytotoxic lymphocytes of NK or more rarely T cells associated with clonal Epstein-Barr . Extranodal NKTCL is rare in Western countries, but in Asia and Central and South America it can account for up to 10% of non-Hodgkin’s . It is an aggressive neoplasm with very poor prognosis. Although the pathogenesis of extranodal NKTCL remains poorly understood, some insights have been gained in the recent years, especially from genome-wide studies. Based on our own experience and knowledge of the literature, we here review some of the genomic and functional pathway alterations observed in NKTCL that could provide a rationale for the development of innovative therapeutic strategies.

1. Introduction represent disseminated nasal NKTCL, knowing that such dissemination can occur early in the clinical course of The term extranodal natural killer/T-cell lymphoma the disease and toward sites that are localizations where (NKTCL) refers to a group of clonal proliferations of nasal NKTCL will metastasize to. Besides the more adverse cytotoxic lymphocytes of natural killer (NK) or, more rarely, clinical features, for which the underlying mechanisms T-cell types, with peculiar clinicopathologic features, arising need to be defined, there are no significant differences mainly as tumors or destructive lesions in the nasal cavity, in age, gender, ethnicity, bone marrow involvement, maxillary sinuses, or palate [1]. More rarely, extranodal hemophagocytosis, or immunophenotypic profiles between NKTCL may present in other extranodal sites such as skin, nasal and nonnasal NKTCL. Very rare cases with primary testis, lung, or gastrointestinal tract and tend to have a more lymph node involvement have also been described [5]. adverse clinical outcome [2–4]. This is particularly true Extranodal NKTCL shows a wide cytological spectrum and when one defines nonnasal cases as extra upper aerodigestive is characterized by frequent features of angioinvasion and tract cases as in the study of Lee et al. which reports angiocentrism, which often result in coagulative necrosis. survival rates of 20% versus 54% for the patients with Typically, tumor cells express cytoplasmic CD3ε,CD2, nasal and upper airway region localizations [4]. However, CD56, lack CD5, CD4, and CD8, and have an activated as noted by several authors, many nonnasal NKTCL might cytotoxic immunophenotype with expression of perforin, 2 Journal of Biomedicine and Biotechnology granzyme B, and TiA1. The cell of origin of these tumors has as in posttransplant B-cell lymphoproliferative disorders been debated. Indeed, the identification of CD3 expression [31]. These B-cell proliferations, like the in vitro infected B- in tumor cells in necrotic lesions has led to the terminology cell-derived lymphoblastoid cell line (LCL), express the full of angiocentric T-cell lymphoma [6–8] adapted in the REAL spectrum of EBV latent (latency III). The latent classification [9], before it was demonstrated that tumor cells phase consists of the maintenance of the EBV genome as express several chains of the CD3 complex in the cytoplasm, a circular episome that is replicated by the cellular DNA but lack T-cell receptors (TCR) and have TCR in a polymerase. Latent type III infection is associated with the germline configuration, consistent with an NK-cell origin expression of six EBV-encoded nuclear antigens (EBNA): [10, 11]. If the majority of NKTCL are likely to originate EBNA1, EBNA2, EBNA2A, EBNA3B, EBNA3C, and EBNA from mature NK cells, a small proportion of cases, with leader (EBNA-LP); three cell surface proteins: latent expression of γδ or αβ TCR appear to derive from cytotoxic membrane protein (LMP) 1, LMP2A, and LMP2B; two EBV- T lymphocytes, reflected in the “NK/T” cell terminology. encoded RNAs: EBER1 and EBER2. Among these proteins, Extranodal NKTCL represents the major group of the EBNA3s are believed to be particularly immunogenic for mature NK cell neoplasms in the recently revised WHO clas- the generation of specific cytotoxic T lymphocytes (CTL). sification of hematolymphoid tumors, which also include the However, similarly to Hodgkin’s lymphoma, NKTCL is aggressive NK cell (ANKL) and a provisional group believed to be in latency II, with a more restricted pattern of chronic NK-cell lymphoproliferative disorder of uncertain of viral proteins expressed, limited to EBNA1, LMP1, and malignant potential, most likely related to T-cell large LMP2 [32]. EBNA1 is required for the maintenance of granular lymphomas [1]. Importantly, both NKTCL and viral episomes and expressed in all latency phases. LMP1 ANKL are Epstein-Barr virus- (EBV-) associated neoplasms is the main transforming protein of EBV. It is essential as the virus is found in their tumor cells [12, 13]. Although for EBV-induced B-cell transformation in vitro, acting like the precise role of the virus in the etiology of the disease is a constitutively activated tumor necrosis factor receptor poorly understood, the study of EBV polymorphism has family member, activating NF-κB pathway and promoting shown that tumor cells are clonally infected as opposed to cell survival. LMP2A and LMP2B are generated by alternative normal nasal tissues [14, 15]. Circulating EBV viral load is an splicing and, although not essential for B-cell transforma- important prognostic factor, and plasma EBV DNA levels can tion, can also promote proliferation and survival. However, also be used for disease monitoring [16]. In this respect, the LMP2 has only been demonstrated at the transcriptional incidence of NKTCL parallels the geographic distribution of level in NKTCL. LMP1 expression is also variable, and when EBV infection with prevalence in the Asian and Central and expressed it is often limited to a subpopulation of tumor cells, South American populations, where it can account for up to possibly under the pressure of host immune surveillance. 10% of non-Hodgkin’s lymphomas [17–19]. Despite these challenging conditions, attempts have been Despite a localized presentation in most patients, extra- made to generate in vitro LMP2-specific CTL using antigen- nodal NKTCL is an aggressive disease with poor prognosis. presenting cells overexpressing LMP2, to treat Hodgkin’s The5-yearsurvivalrateislessthan50%.Intheabsence lymphoma and NKTCL patients [33]. The cytotoxic activity of effective treatment, the median survival for advanced- of these LMP2-specific CTL have been confirmed against stage disease is only 6–12 months [19–22]. The retrospective NKTCL-derived cell line, which led to the discovery of a International Peripheral T-cell Lymphoma project recently unique alternative transcript of LMP2 (LMP2-TR) that uses reported a median overall survival of 7.8 months for NKTCL, a new promoter located in the terminal repeat region of corresponding to the poorest survival among all T-cell the episomal EBV, not expressed in B-LCL [34]. LMP2- lymphoma entities [2]. Therefore, despite progress with TR may constitute a promising target for adoptive cellular combined field radiotherapy and chemotherapy, autologous immunotherapy in NKTCL. bone marrow transplantation and the promising effect of L- EBV is a B-lymphotropic virus, infecting B cells through asparaginase treatment in relapsed cases [16, 23], NKTCL interaction with its cellular receptor CD21, and establishing remains difficult to cure, and the need for alternative a lifelong infection in more than 90% of the human adult therapeutic strategies has prompted researchers to explore population. Although the precise mechanism involved in oncogenic pathways involved, to provide new molecular tar- NK- or T-cell infection is unknown, passive acquisition of gets. This review will focus on the these potential molecular CD21 in the NK/T-cells by membrane fragment exchange pathways that have been implicated in the physiopathology during cytotoxic interaction, a process known as trogo- of NKTCL, in particular through the lights shed by several cytosis, has been proposed [35, 36]. Chronic active EBV recently reported genome-wide profiling studies [24–30]. infection (CAEBV) was first recognized as severe illness related to chronic or persistent EBV infection [37, 38]. CAEBV is a life-threatening disease characterized by infec- 2. EBV Infection and Viral Protein Expression tious mononucleosis-like symptoms with virus-associated hemophagocytic syndrome. Like in NKTCL, clonal prolifer- Several lines of evidence point at EBV as a major player in ations of EBV-infected NK- or T-cells are seen in patients the pathogenesis of NKTCL. First of all, when dealing with with CAEBV, making this disease more likely a chronic an EBV-associated malignancy, one can think of NKTCL as a lymphoproliferative disorder or a premalignant stage as some potentially highly immunogenic lymphoma that could bene- CAEBV patients can actually develop subsequent NKTCL fit from cellular immunotherapies targeting the viral antigens [39]. Whether the EBV-host interaction may play a role Journal of Biomedicine and Biotechnology 3 in the development of NKTCL is still a pending question. identified from the initial description of ANKL [56, 57], the Performing comparison of EBV and cellular gene expression cytotoxic activity of the NKTCL tumor cells has not been profiling in NKTCL- and CAEBV-derived cell lines, Zhang particularly investigated due to the difficulty to isolate these et al. reported the transcription of lytic phase genes such cells. as BZLF1, BARF1, BFLF2, and BDLF3, despite the absence of virion DNA production and cellular gene signature 4. Survival/Apoptosis implicating mainly cell cycle and apoptosis-related genes such as TNFRSF10D, CDK2, Hsp90, IL12A, and PDCD4 The mechanisms by which NKTCL cells survive and escape [30]. Beside the expression of latency II genes, expression immune surveillance are unknown. One way for an NKTCL in NK/T-cell lines, of lytic phase genes (such as BZLF1) tumor cell to escape anti-EBV immunity is to lower its capable to interact with multiple cell cycle control proteins expression of EBV antigens, particularly LMPs proteins. It is intriguing. EBV may exert oncogenic effects through the is also known that cytotoxic effector cells have a proper production of such as Interleukin 9 (IL-9) [26] way to resist to their own cytotoxic agents [58]. The main and IL-10 [40]. EBV-induced production of IP10/MIP2 cytotoxic pathway used by NK and CTL involves the release may contribute to vascular damage and necrosis from specialized granules of cytotoxic molecules including [41]. Obviously, the way viral gene products interact with perforin and granzymes, triggering a process leading to DNA cellular host needs to be clarified and may lead fragmentation and apoptosis. In particular, granzyme B to novel targets for therapies. (GZMB), by activating directly or indirectly caspase-3, leads to rapid execution of apoptosis. SERPINB9 (also known as PI9) is a GZMB-specific serine protease inhibitor that can ff 3. NK Cell Antigens and Cytotoxic Activity protect e ector cells from their own cytotoxic activity. It has been shown that SERPINB9 can make hepatocytes resistant Irrespective of their NK, αβ-, or γδ-T-cell lineage, NKTCL is to lysis by CTL or NK cells [59] and may participate to the a lymphoma of activated cytotoxic lymphocytes as evidenced mechanism for tumor escape in NKTCL [60]. Interestingly, by the expression of cytotoxic molecules such as perforin, its loss of expression was described as a poor prognostic granzyme B, and TIA1 [42]. Whereas T cells use their TCR factor in a study of 48 NKTCL patients [20]. for antigen recognition and control of their specific cytotoxic Although it seems that tumor cells are resistant to activity, NK cells use MHC class I-specific NK cell receptors the killing via GZMB, NKTCL are frequently associated (NKR) for this purpose [43]. NK cells are part of the innate with zonal tumor cell death, tissue necrosis, and vascular immune system involved in the immunosurveillance [44]. damage. The production of chemokines like CXCL9 (Mig) Engagement of inhibitory NKR by self-MHC class I on and CXCL10 (IP10), in response to interferon γ released potential target cells inhibits cytotoxicity whereas loss of by activated tumor cells, may contribute to the observed MHC class I expression due to transformation or viral infec- damages [41, 61]. Although Fas (CD95) as well as tion, results in a loss of this inhibition. There are two types (FASL/CD95L) are frequently well expressed in NKTCL cells, of NKR: the killer immunoglobulin-like receptors (KIR) and mutations of the FAS gene are observed in 50 to 60% of the killer cell lectin-like receptors (KLR or CD94/NKG2 cases, most likely contributing to resistance to apoptosis complexes). KLR as well as other NK cell markers like CD56 [62]. Indeed, most of the FAS gene mutations are frameshift can also be expressed by αβ-orγδ-cytotoxic T cells. The mutations arising in the death domain, leading to mutated KIR locus located on human 19, exhibits a proteins on the cell surface, unable to transduce the apoptotic substantial haplotypic and allelic diversity [45, 46]. The KIR signal [63]. High expression of FASL is also a way for haplotypes have been separated into two groups, containing tumor cells to evade immune response by deleting Fas- from7to12genes[47]. The expression of KIR at the expressing infiltrating T cells. In line with these observations, cell surface is clonally distributed, meaning that a clonal NKTCL has long been known as resistant to combination NK/T-cell population is expected to express a restricted KIR chemotherapy. This resistance is also complicated by the repertoire as shown in NKTCL [48–50]. Another example high expression of p-glycoprotein, encoded by multidrug of the interest of KIR in malignant lymphomas is given by resistance gene 1 (MDR1)thatactsasanenergy-dependent KIR3DL2 that proved to be a valuable tool in the diagnosis, efflux pump for various drugs [64]. and perhaps a clinical target, of Sezary´ syndrome, a cuta- Very recently, survivin (BIRC5), an inhibitor of apop- neous CD4+ T-cell lymphoma with systemic dissemination tosis frequently involved in tumor oncogenesis, was found [51–53]. KLR are C-type lectin receptors that precede the overexpressed in NKTCL [28]. The authors proposed that expression of KIR during NK cell development. They consist survivin could be a useful therapeutic target in NKTCL. of molecules of the NKG2 family such as NKG2A (KLRC1), In in vitro studies, they showed that Terameprocol, a NKG2C (KLRC2), or NKG2E (KLRC3), form heterodimer survivin inhibitor, could downregulate survivin expression with earlier expressed CD94 at the surface of maturing and induced apoptosis in NK cell lines. NK cells [54]. In addition to immature NK cells, a subset of mature NK cells also lack CD94/NKG2 expression as 5. Cytogenetic Analysis a consequence of the clonal diversification phenomenon. Interestingly, expression of CD94 has been associated with Lymphomas arise from clonal expansion of transformed a better prognosis in NKTCL [55]. Although NK activity was lymphoid cells through the accumulation of genetic lesions. 4 Journal of Biomedicine and Biotechnology

Currently, no genetic abnormalities specific for NKTCL have frequently involved in sporadic Wilm’s tumors, led to the been identified. Cytogenetic analyses of NKTCL are difficult identification of the HACE1 gene [91]. It encodes a member because of necrosis, small-size samples, and contamination of the HECT family of E3 ubiquitin ligases that tag specific by inflammatory reactive cells. Despite these difficulties, target proteins to degradation by the proteasome or to several studies using comparative genomic hybridization control their subcellular localization [85]. Because of their (CGH) and loss of heterozygosity (LOH) techniques have involvement in controlling crucial signaling pathways, E3 been reported [65–70]. Altogether, these studies identified ubiquitin ligases appear as important regulators of cancer gains at 1p, 6p, 11q, 12q, 17q, 20q, Xp, development and therapy. It is downregulated in multiple and losses at 6q, 11q 13q, and 17p. In particular, the human cancers and maps to a prominent tumor-suppressor most frequent deletion was observed at 6q21–25 in all but region of LOH in many tumors including lymphomas. onestudy.Sunetal.triedtodefineaminimaltumor HACE1−/− mice are also prone to spontaneous development suppressor gene-containing region involved in del6q25 and of various types of cancers [90]. Our integrated genomic and identified a 2.6 Mb interval located between TIAM2 and transcriptomic analysis of NKTCL tumor samples and cell SNX9 genes [69]. More recently, progress in the DNA chip lines has shown downexpression of HACE1 gene irrespective technology allowed the development of genome-wide array- ofthepresenceofdel6q21alteration[24]. In addition, based CGH (aCGH) giving access to better resolutions. we could show by methylation-specific PCR and product The first report, from Nakashima et al., performed with sequencing (data not shown) that hypermethylation of CpG- homemade arrays with 1.35 Mb resolution, studied 10 of 177 island located directly upstream of HACE1 locus, is ANKL and 17 NKTCL cases and reported differences in their responsible of the silencing of the diploid gene or the genomic alteration patterns (see Table 1)[27]. Loss of 7p remaining allele. Although the mechanism of antitumor (40%) and 17p13.1 (40%) and gain of 1q (43%) occurred action of HACE1 is still unclear, it has been shown that more frequently in ANKL whereas loss of 6q did not. On the overexpression of HACE1 in the 293T cell line inhibits cell other hand, loss of 6q21–q22.1 (35%), 6q22.33–q23.2 (47%), proliferation via the degradation of phosphorylated cyclin 6q25.3 (29%), and 6q26-q27 (35%) were more frequent in D1 [90]. This suggests a possible mechanism for HACE1 to NKTCL. Other alterations in NKTCL compared to ANKL regulate cell cycle exit by reducing cyclin D1 levels. Existence include gain in 2q and loss of 1p36.23–p36.33, 2p16.1– of other HACE1 targets is possible as suggested by the recent p16.3, 4q12, 4q31.3–q32.1, 5p14.1–p14.3, 5q34–q35.3, and identification of retinoic acid receptor beta 3 as an HACE1 11q22.3–q23.3. Two recent studies extended these findings interacting protein [92]. by comparing submegabase resolution aCGH and gene expression profiling on NK cell lines as well as NKTCL tumor samples [24, 71]. These two studies emphasize recurrent 6. Cell Signaling Pathways genomic abnormalities observed in about half of the patients: gain of 1q21–q44, and losses of 17p11.2–p13.3 and 6q21. Although the anomaly of signaling pathways involved in the In particular, this region of del6q21 contains four candidate pathogenesis of NKTCL is not deciphered, progress has been tumor suppressor genes, PRDM1, ATG5, AIM1, and HACE1, made in the recent years that will help to define candidate which decreased expression was confirmed at the RNA level. therapeutic targets. In their study, Iqbal et al. found mutations and methylation in PRDM1, ATG5,andAIM1 in NKTCL cell lines [71]. ATG5 is part of the autophagy pathway implicated both in 6.1. Jak-Stat Pathways. Signal transducers and activators of apoptosis and in the maintenance of energy homeostasis transcription, STATs, are transcription factors activated in during starvation [72]. The role of autophagy in onco- response to cytokines or growth factors [80]. The activation genesis is, however, the object of controversy [73]. AIM1 of STAT signaling pathways requires tyrosine phosphoryla- which stands for “absent in -1” is still poorly tion of the STAT proteins that results from their association characterized but was reported as a good tumor suppressor with growth factor receptors having intrinsic tyrosine kinase gene candidate in malignant melanoma, exerting its effects activity, or through recruitment of members of the Janus through interactions with the cytoskeleton [74]. PRDM1 is a kinase (JAK) family to activated surface receptors. A direct transcriptional regulator, initially described as a suppressor link between STAT signaling and oncogenesis was established of beta-interferon gene expression, that is associated with when it was shown that constitutive STAT activation by the terminal differentiation of B lymphocytes and T-cell oncogenic tyrosine kinases from Src or Abl families, directly homeostasis and function [75, 76]. It was found mutated in participates to cell transformation [93, 94]. Accordingly, a some diffuse large B-cell lymphomas, and it was concluded large number of tumors, both in primary cells as well as that its inactivation contributes to lymphomagenesis by in tumor-derived cell lines, display constitutive activation of blocking differentiation of postgerminal center B cells to STAT factors. In particular, STAT3 role in oncogenesis is well plasma cells [77]. Loss-of-function due to mutations as well documented in anaplastic large cell lymphoma where STAT3 as transcriptional inhibition by DNA methylation observed activation was shown to provide growth advantage and in NK cell lines, suggest a tumor suppressor role of PRDM1 resistance to apoptosis of ALK+ tumor cells [81, 95, 96]. In in NKTCL [71]. NKTCL, STAT3 was found constitutively activated, by phos- HACE1 is another candidate tumor suppressor gene [24, phorylation on Y705, and localized in the nucleus in 90% 90]. Characterization of the chromosome 6q21 breakpoint, of the patients studied [24, 82]. Inhibition of endogenous Journal of Biomedicine and Biotechnology 5

Table 1: Recurrent genomic alterations in extranodal NKTCL from published data.

Chromosomal Frequency (%) location Huang et al. Iqbal et al. 2009 Nakashim et al. Yoon and Ko Ko et al. 2001 Siu et al. 2000 Siu et al. 1999 2010 [24] [71] 2005 [27] 2003 [70] [66] [67] [68] Gains 1q21–q44 50 50 50 20 2q13-q14 26 24 29 2q31.1–q32.2 20 24 43 6p25–p11.1 40 25 40 7q11.2–q34 50 32 24 20 7q35-q36 60 40 40 17q21.1 20 50 29 40 20pter-qter 30 45 50 Losses 6q16–q2540503880 4925 11q23.1 30 13 29 31 20 11q24-q25 40 25 20 13q14.11 30 27 25 14 60 17p13.3404540 434020

Table 2: Potential Therapeutic targets for extranodal NKTCL.

Pathways Genes Expression Chromosomal location References EBV LMP2-TR Up N.A. [32] Survival/apoptosis CCND3 Down 6p21.1 [69] SERPINB9 Down 6p25 [19, 57] FASL Up 1q23 [60, 78] TNFAIP3 Down 6q23 [69, 79] Cell signaling pathways JAK-STAT STAT3 Up 17q21 [80, 81] JAK2 Up 9p24 [69, 81] IL10 Up 1q31-q32 [81, 82] AKT AKT1/2/3 Up 14q32.3/19q13.1/1q44 [69, 70] NOTCH NOTCH1 Up 9q34.3 [24, 83] WNT β-CATENIN Up 3p22–p21.3 [24, 69] PDGF PDGFRA Up 4q11–q13 [69] PDGFA/B Up 7p22/22q12.3–q13.1 [69] Angiogenesis HGFR (MET) Up 7q31 [78] VEGFR2 Up 4q12 [24, 69] VEGFA Up 6q12 [24, 69] HIF1α Up 14q21–q24 [24, 70, 84] Tumor suppressor genes del6q21 PRDM1 Down 6q21–q22.1 [70] ATG5 Down 6q21 [70] AIM1 Down 6q21 [70] HACE1 Down 6q21 [69, 85] Other pathways/genes TP53 Down 17p13.1 [86, 87] TP73 Down 1p36.3 [88] AURKA Up 20q13 [24, 89] N.A.: not applicable 6 Journal of Biomedicine and Biotechnology activated STAT3 in NKTCL-derived cell lines, using trans- like in PTCL NOS (PTCL not otherwise specified) [83], an ducible dominant-negative STAT3, leads to growth arrest and autocrine feedback loop may explain the presence of the apoptosis inhibition [82]. These results are consistent with phosphorylated PDGFRα observed in all the 13 NKTCL the known targets of STAT3 transcriptional activities that cases examined. The potential of PDGF signaling pathway include survivin, cyclin D1, BCL-XL,cMYC,vasculargrowth in NKTCL cell proliferation is illustrated by the dramatic factor (VEGF), IL-10, and IL-6 [97]. Importantly, STAT3 dose-dependent inhibition of MEC04 cell growth observed activation promotes the production of immunosuppressive in cultures performed the presence of imatinib mesylate [24]. factors not only by the tumor cells but also by cells of the microenvironment through mediators such as VEGF or IL-10, activating STAT3 in these bystander cells that 6.4. Other Signaling Pathways. Pathways enriched in the gene in turn restrains antitumor immune response [84, 98]. signature of NKTCL include those of the NOTCH, WNT, Targeting STAT3 and/or JAK2 for cancer immunotherapy and NFκB signaling pathways [24, 25, 30]. However, and may therefore be promising. particularly in this tumor where necrosis is associated with strong infiltration of mesenchymal and lymphoid cells, it is sometimes difficult to attribute the differentially expressed 6.2. Angiogenesis Pathway. NKTCL is characterized by angio- genes to the tumor cells rather than to the microenvironment centric growth and vascular damages with invasion of vessel cells. In addition, differential expression needs confirmation walls by lymphoma cells. In this context, a search for genes in terms of biochemical activation. In particular, activation associated with angiogenesis seems essential. The recent gene of the WNT pathway, comprising genes involved during expression profiling studies have recorded overexpression the development and in oncogenesis, can be evidenced of genes related to angiogenesis in NKTCL as compared by the nuclear translocation of β-catenin. However, no to other peripheral lymphomas or normal NK cells nuclear expression of β-catenin could be observed in the [24, 25]. Among those, one finds VEGFA an important neoplastic cells in our study by Huang et al. [24], making the downstream product of STAT3, and its receptor VERGFR2 targeting of WNT pathway of poor interest for therapeutic (KDR), both genes are upregulated, a finding confirmed purpose. On the other hand, activation of the NOTCH by the immunohistochemical detection of VEGFα and pathway has been validated by Iqbal et al. [25]. NOTCH its receptor in tumor cells. As mentioned previously, the signals regulate development and differentiation of adult self- production of VEGF by tumor cells not only may be used renewing cells, including T cells. Gamma-secretase is a crit- for autocrine growth and survival but also to maintain ical component of the NOTCH signal transduction pathway an immunosuppressive microenvironment by activating the [100]. Showing that inhibitors of γ-secretase can block the STAT3 pathway. Vascular destruction observed in nasal type proliferation and survival of NK cell lines in vitro, was used NKTCL results in hypoxia and the transcription activation for validation of NOTCH implication. Interestingly, PTEN of HIFα (hypoxia-inducible factor 1), a transcriptional is a tumor suppressor gene encoding a lipid phosphatase activator that stimulates the expression of a number of that antagonizes the activation of the PI3K/AKT pathway. genes implicated in angiogenesis (including VEGFA and NOTCH1 controls a transcriptional network that leads to VEGFR2)andinoxygenhomeostasis[78]. Also observed is activation of PI3K/AKT signaling and downmodulation of the upregulation of another important gene in angiogenesis, PTEN expression. NOTCH signaling and PI3K/AKT pathway the c-MET proto-oncogene that encodes the tyrosine kinase act synergistically to maintain oncogenic activity in T-cell cell surface receptor for the hepatocyte growth factor (HGF). acute lymphoblastic leukemia [101]. PI3K/AKT was found HGF is a pleiotropic acting as an antiapoptotic, activated in microarray analysis of NKTCL, and nuclear a promigratory, and a proliferating factor for a number expression of phosphorylated-AKT was found in the nucleus of tissues. Interestingly, MET may be implicated in the of most NKTCL samples. NFκBisamasterregulatorthat prevention of FAS-mediated apoptosis of the FAS-expressing controls the expression of a number of genes. Because EBV NKTCL tumors cells. This relies on the YLGA aminoacid is known to activate NFκBthroughLMP-1and/orTRAF motif located near the N-terminal region of MET that signaling [79], upregulation of NFκBpathwayinNKTCL specifically binds to the extracellular portion of FAS and acts versus normal NK cells is not unexpected. Signaling by as a FASL antagonist and inhibitor of FAS trimerization [99]. the transcription factor NFκB involves its release from its inhibitor IκB, followed by its translocation into the nucleus. 6.3. PDGFR Pathway. The platelet-derived growth factor Nuclear detection by immunohistochemistry of RelA, the receptor- (PDGFR-) signaling pathway was also found protein constituting the most abundant form of NFκB, activated in NKTCL cells [24]. The overexpression of further supports the activation of this pathway in NKTCL. PDGFRA mRNA in NKTCL compared to normal NK cells in Interestingly, the tumor necrosis factor-α-induced protein microarray data is confirmed by the expression of PDGFRα gene, TNFAIP3, an inhibitor of NFκB activity, was also found and its phosphorylated form in primary tumors, shown downregulated in NKTCL. This gene is located in 6q23, the by immunohistochemistry. Neither genomic abnormalities region of recurrent loss discussed above, and loss of function in the PDGFRA locus in 4q11–q13 nor mutations in the of TNFAIP3 have also been reported in Hodgkin’s lymphoma coding sequence or anomalies in the promoter region and other B-cell lymphomas [86, 102]. Surprisingly, the could be evidenced. The mechanism responsible for the NFκB pathway genes were not enriched in the NKTCL gene activation of the PDGFR remains therefore unclear, but signature in the recent study of Iqbal et al. [25]. Questions Journal of Biomedicine and Biotechnology 7 remain, therefore, to clarify the value of this pathway to TP53. Katayama et al. showed that TP53 is phosphorylated by identify therapeutic targets for NKTCL. AURKA, inducing its ubiquitination by MDM2 and its pro- teasomal degradation [107]. Thus, AURKA is a key regulator of TP53 pathway, and the AURKA inhibitor MK8751 induced 7. Other Pathways and Candidate Target Genes cell cycle arrest and apoptosis in human cell lines, including NKTCL-derived cell lines [25]. AURKA represent, therefore, Many other genes are found differentially expressed or an interesting potential therapeutic target for NKTCL. targets for mutations or methylations in NKTCL when compared to normal NK cells (see Table 2). The list includes a number of oncogenes or tumor suppressor genes associated 8. Conclusion with many other tumors. TP53 is a well-known tumor ANKL and NKTCL are EBV-associated malignancies of cyto- suppressor gene that causes cells with damaged DNA to toxic lymphocytes with poor prognosis and lack of efficient arrest at G1 phase of the cell cycle. TP53 is mutated therapies. Their aggressive behavior and poor response to in many cancers, and the frequency of NKTCL-mutated chemotherapy make of paramount importance the search cases varies from 20 to 60%. TP53 mutated cases have for novel therapeutic targets in the treatment of these been associated with more advanced cases, suggesting that lymphomas. NKTCL is a rare disease although more frequent TP53 mutation represents a secondary oncogenic event in Asia and South America, and the insufficient supply of rather than a triggering mechanism for the development of tumor samples limits the development of an intense research NKTCL [87]. Nevertheless, TP53 is found underexpressed in that field. In this context, malignant NK/T-cell lines in NKTCL transcriptomic analyses, and the observation represent valuable tools to study these pathologies [108]. that EBNA1 promotes TP53 degradation [88]hastobe Genome-wide studies have generated new data improving considered to make TP53 pathway a possible target for our understanding of the disease. Indeed, candidate tumor NKTCL therapy. TP73 belongs to the family of p53-related suppressor genes, such as PRDMI, ATG5, AIM1,orHACE1, proteins, which is involved in cell cycle arrest and apoptosis. which can be inactivated by deletion and by methylation, Methylation of TP73 has been reported in 94% of NKTCL have been identified. The molecular signature of NKTCL and has been proposed as a biomarker to detect NKTCL is distinct from that of other T-cell lymphoma subtypes. involvement and [103]. MYC family genes encode Compared to normal NK cells, NKTCL is characterized by multifunctional nuclear phosphoproteins that function as activation of several pathways—PDGFRA, VEGFR, AKT, transcription factors to regulate expression of genes involved JAK-STAT, and NOTCH—which might represent targets for in cell cycle progression such as CCNA2, CDKN1A,and novel therapeutic options. Before settingup clinical trials, CDKN2B. Although frequent in hematopoietic and solid extensive experimental validation of the potential target will tumors, mutations, amplification, and translocation of this have to be undertaken using the available models. In this oncogene have not been found in NKTCL. However, MYC respect, the study of tumor engrafting and development in expression appears to be upregulated in the gene signature of immunocompromised mice injected with NKTCL cell lines NKTCL. or tumor fragments [82, 109] can be valuable models to test Adhesion and cell-to-cell interaction molecules may new potential drugs and their in vivo activity. One can hope play an important role in tumor growth and homing in that the efforts of the researchers working to understand this view of the particular tropism of NKTCL for extranodal pathology will soon lead to progress in the treatment of these sites. The molecular signatures reported for NKTCL in lymphomas. comparison with normal NK cells include overexpression of genes of the cadherin family (CDH1), of the integrin family(VCAM1,ITGA7,ITGA9,andITGB4),andofthe Acknowledgment family (SIGLEC1, SIGLEC 9, SIGLEC11, and SIGLECP3). 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